In resting T-cells, the ETS1 gene is expressed at high levels and, upon activation of T-cells, ETS1 gene products are decreased to low levels, suggesting that ETS1 may play a dominant role in differentiation and cessation of cell growth. To identify if ETS1 gene products have any tumor-suppressive activity, the human ETS1 expression vector was transfected into the human colon cancer cell line, DLD-1, which shows no detectable expression of ETS1. We obtained five independent cell lines expressing ETS1 at different levels. These transfectants showed reduced tumorigenicity in colony formation assays in soft agar and in nude mice assays. The degree of suppression of tumorigenicity was dependent on the levels of ETS1. Since overexpression of ETS1 in NIH/3T3 cells has been shown to increase tumorigenicity, it appears that the oncogenic and anti- oncogenic activities displayed by ETS1 are dependent on the cell types. Using Western blot analysis of a two-dimensional gel, we have identified a decrease of keratin 8 (K8) protein in one transfectant cell line expressing abundant ETS1. Levels of K8 mRNA did not change between the transfectant and control cell lines. Experiments are in progress to characterize the mechanisms involved in a decrease of K8 levels and to identify putative target genes for ETS1 in colon cancer cells.